Atom Oxe Tine

Pediatr Drugs 2009; 11 (3): 203-226
1174-5878/09/0003-0203/$49.95/0
ADIS DRUG EVALUATION
2009 Adis Data Information BV. All rights reserved.
Atomoxetine
A Review of its Use in Attention-Deficit Hyperactivity Disorder in
Children and Adolescents
Karly P. Garnock-Jones and Gillian M. Keating
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia,
Pennsylvania, USA
Various sections of the manuscript reviewed by:
J. Graham, Department of Psychiatry, University of Dundee, Dundee, UK; D.E. Greydanus, Department of Pediatrics and Human
Development, Michigan State University, Kalamazoo, Michigan, USA; F. Levy, School of Psychiatry, University of New South Wales, Sydney,
New South Wales, Australia.
Data Selection
Sources: Medical literature published in any language since 1980 on atomoxetine, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database
of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished
data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were atomoxetine and [(attention deficit hyperactivity disorder or ADHD) and (infants or children or
adolescents)]. Searches were last updated 10 February 2009.
Selection: Studies in pediatric patients with attention-deficit hyperactivity disorder who received atomoxetine. Inclusion of studies was based mainly on the methods section of
the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also
included.
Index terms: Atomoxetine, attention-deficit hyperactivity disorder, ADHD, children, adolescents, pharmacoeconomics, pharmacodynamics, pharmacokinetics, therapeutic
use, tolerability.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
2. Pharmacodynamic Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2.1 Effects on Neurotransmitter Transporters and Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2.2 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
3. Pharmacokinetic Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
3.2 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
3.3 Special Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
4.1 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
4.1.1 Short-Term Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
4.1.2 Longer Term Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
4.1.3 In Stimulant-Naive Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
4.2 Comparisons with Stimulants or Standard Current Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
4.3 In Patients with Co-Morbid Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
5. Tolerability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
5.1 Specific Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Garnock-Jones & Keating
204
7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

8. Place of Atomoxetine in the Management of Attention-Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Summary
Abstract
Atomoxetine (Strattera) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder
(ADHD).
Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and
standard current therapy and does not differ significantly from or is noninferior to immediate-release
methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS methylphenidate (hereafter referred to as osmotically released methylphenidate) and
extended-release mixed amfetamine salts.
Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a
negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly
useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do
not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in
children and adolescents.
Pharmacologic
Properties
The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of
presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity
for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and
studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons,
such as the fronto-cortical subsystem.
Atomoxetine was generally associated with statistically, but not clinically, significant increases in both
heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected
height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data
suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than
methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD.
Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It
undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP)
2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination
of atomoxetine than extensive metabolizers.
Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as
paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among
poor CYP2D6 metabolizers.
Therapeutic Efficacy
Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and
adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated
efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into
the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine
efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded
well to atomoxetine treatment.
Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in
children and adolescents with ADHD with regard to efficacy, and was significantly more effective than
standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral
counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts.
The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and
symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration.
Pediatr Drugs 2009; 11 (3)
Atomoxetine: A Review
205
Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and
long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy.
Tolerability
Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events
included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of
adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients
discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to
be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared
better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers.
Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and
insomnia appeared more common among stimulant recipients.
A black-box warning for suicidal ideation has been published in the US prescribing information, based on
findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of
suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to
atomoxetine treatment.
Pharmacoeconomic
Evaluation:
Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants,
or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The
incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as
shown in several Markov model analyses conducted from the perspective of various European countries,
with a time horizon of 1 year.
1. Introduction
Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder, characterized by one or both of its subtypes
(inattention and hyperactivity/impulsiveness).[1,2] Symptoms may
manifest as early as 3 years of age; however, most diagnoses occur
when the patient is aged 710 years.[3] Approximately half of
childhood ADHD patients show symptomatic features continuing
into adulthood.[1] ADHD has a prevalence of 39% in children and
adolescents in the US,[1] and 48% worldwide.[4] European rates
appear lower than US rates; however, this has been described as an
effect of using diagnostic criteria based on the International
Classification of Diseases (ICD), as opposed to Diagnostic and
Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)[5]
criteria.[1] Male sex, low socioeconomic status, and young age are
all associated with a higher prevalence of ADHD.[6]
Co-morbid psychiatric disorders are common among patients
with ADHD, including oppositional defiant disorder (ODD),
conduct disorders, mood disorders, and anxiety disorders.[2,6]
More than two-thirds of children with ADHD have a co-morbid
condition.[2]
The etiology and pathophysiology of ADHD are, thus far,
unknown; however, genetic and developmental factors have been
implicated, as have, to a smaller degree, environmental and social
factors.[2,4,6] Dopamine and norepinephrine (noradrenaline)

abnormalities are believed to be associated with ADHD, as are
alterations in regional cerebral volumes and reduced metabolism in the prefrontal cortex and striatal regions.[2,4,6]
It has been demonstrated that ADHD patients use significantly more health services than children without ADHD,
both before and after diagnosis.[7] The total financial burden of
ADHD to patients and their families in the year 2000 in the US
was estimated to be $US31.6 billion.[2]
Currently, where pharmacologic treatment is deemed appropriate, recommended ADHD treatments include methylphenidate, dexamfetamine, and atomoxetine (Strattera).[8]
Lisdexamfetamine is also approved for the treatment of
ADHD.[9] Of these, methylphenidate, dexamfetamine, and lisdexamfetamine are all CNS stimulants.[8,9] There are several
concerns with stimulant use, including the risk of growth retardation, development of tics, and sudden cardiac death, as
well as a potential for abuse or misuse.[2]
Atomoxetine is an orally administered selective norepinephrine
reuptake inhibitor that is approved for the treatment of ADHD in
various countries including the US[10] and the UK.[11] It is not
classified as a stimulant, and is not a controlled substance in the
US. This article reviews the pharmacologic properties and clinical
206
profile of oral atomoxetine in children and adolescents with

ADHD.
2. Pharmacodynamic Properties
Atomoxetine is a (-) isomer of an ortho-methylphenoxy analog of nisoxetine, and is a derivative of phenoxypropylamine.[12]
Its mechanism of action in the treatment of ADHD is unclear,
but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex, resulting in increased noradrenergic transmission, important for
attention, learning, memory, and adaptive response.[13,14]
2.1 Effects on Neurotransmitter Transporters
and Receptors
Atomoxetine has a high affinity and selectivity for norepinephrine transporters, as demonstrated in radioligand binding studies in rat brain synaptosomes,[12,15] as well as in clonal cell lines
transfected with human neurotransmitter transporters.[16] The affinity constant (Ki) values for atomoxetine inhibition of norepinephrine, serotonin, and dopamine transporters (in MDCK
and HEK 293 cells) were 5, 77, and 1451 nmol/L.[16] Atomoxetine was associated with a much lower affinity (Ki >1 mmol/L)
for choline, GABA, and adenosine transporters,[16] as well as
many other neurotransmitter receptors, ion channels, second
messengers, and brain/gut peptides.[16]
In vitro radioligand binding studies of atomoxetine in the
human brain have demonstrated that it has little or no affinity
for various neurotransmitter receptors.[17] Ki values for atomoxetine binding to muscarinic, a-adrenergic, histamine H1,
and serotonergic (5-HT1A and 5-HT2) receptors were
94010 900 nmol/L; for atomoxetine binding to dopamine D2
receptors the Ki was >35 000 nmol/L.[17]
When norepinephrine and serotonin depletion was induced
in the rat brain in vivo, using the transporter-specific neurotoxins p-CA and DSP-4, atomoxetine was shown to inhibit the depletion of norepinephrine, but not serotonin, in a dose-dependent
manner.[16] Methylphenidate did not inhibit either transporter,
leading to normal depletion of both neurotransmitters.[16]
Localization studies, using quantitative autoradiography in
the rat brain, suggest that atomoxetine preferentially binds to
areas of known high distribution of noradrenergic neurons,
such as the fronto-subcortical system, which controls attention
and motor behavior.[18,19]
In rats, intraperitoneal atomoxetine significantly (p < 0.025)
increased extracellular norepinephrine and dopamine levels in the
prefrontal cortex by up to 290% and 323% of basal levels; serotonin
levels did not significantly differ from baseline.[16] Extracellular
dopamine levels in the nucleus accumbens and striatum remained

constant. Methylphenidate significantly (p < 0.05) increased extracellular norepinephrine and dopamine levels in the prefrontal cortex, and dopamine levels in the nucleus accumbens and striatum,
indicating a potential difference from atomoxetine in mechanism
of action.[16] It was hypothesized that the inhibition of dopamine
uptake in the prefrontal cortex, but not in the dopamine transporter-rich nucleus accumbens and striatum, was due to baseline
nonselective dopamine uptake by norepinephrine transporters in
the prefrontal cortex.[16] The absence of extracellular dopamine
accumulation in the nucleus accumbens and striatum suggests that
atomoxetine is unlikely to produce tics or have abuse potential.[16]
Atomoxetine also selectively inhibits norepinephrine uptake
in humans.[20] Four healthy male volunteers received atomoxetine 20 mg twice daily for 1 week, following a week of placebo
administration. When an infusion of norepinephrine was
administered, the mean pressor response for atomoxetine
versus placebo was 12.4 versus 5.2 mmHg per microgram of
norepinephrine per minute (p = 0.054).[20] The increase with
atomoxetine on day 1 was 261% greater than that observed with
placebo.[20] There was a significant correlation between the
pressor response to norepinephrine and the plasma concentration of atomoxetine (p = 0.002).[20] In contrast, when an
infusion of tyramine was administered, the mean pressor response for atomoxetine versus placebo treatment was 4.5 versus
7.9 mmHg per milligram of tyramine per minute (p = 0.003),
and the increase with atomoxetine on day 1 was 70% of that
observed with placebo.[20] Serotonin uptake into platelets was
not affected by atomoxetine administration in this study.[20]
A randomized, double-blind, crossover study using transcranial magnetic stimulation in nine healthy volunteers demonstrated that both atomoxetine 60 mg and methylphenidate
30 mg significantly (p < 0.05) decreased cortical inhibition and
increased cortical facilitation to extents that did not significantly differ between treatments, indicating the possibility
of a shared cortical target for ADHD treatment.[21]
2.2 Other Effects
Atomoxetine was associated with modest increases in heart

rate and BP in children and adolescents with ADHD, according
to the results of a pooled analysis of clinical trial data.[22] In the
short term (up to 9 weeks therapy), significantly greater increases
in mean heart rate (+7.8 vs +1.5 beats/minute [bpm]; p < 0.001)
and mean diastolic BP (DBP; +2.1 vs -0.5 mmHg; p = 0.002) were
seen with atomoxetine than with placebo; there was no significant between-group difference in the change in systolic BP (SBP).
Patients receiving atomoxetine for 1 year had increases in mean
heart rate of <10 bpm and mean increases in BP that were small
and not considered to be of clinical significance.[22] The incidence of abnormally high heart rate or BP in atomoxetine
recipients is discussed in section 5.1. Atomoxetine treatment was
not associated with QT prolongation in these clinical trials.[22]
Heart rate appears to increase to a greater extent among
atomoxetine recipients compared with stimulant recipients (section 4.2). In a study comparing the efficacy of atomoxetine with
that of the extended-release methylphenidate formulation OROS
methylphenidate (hereafter referred to as osmotically released
methylphenidate), recipients of atomoxetine showed a significantly
greater change in heart rate (+6.4 vs +3.0 bpm; p < 0.05).[23]
Another study demonstrated a greater increase in heart rate among
atomoxetine versus immediate-release methylphenidate recipients
(+8.51 vs +4.76 bpm; p = 0.005).[24] Where reported in other active
comparator trials, atomoxetine did not differ significantly from
immediate-release methylphenidate[25] or extended-release mixed
amfetamine salts[26] with regard to the increase in heart rate.
Atomoxetine is unlikely to lead to abuse.[27,28] A randomized, double-blind, crossover trial in 16 healthy volunteers
who were nondependent light drug users compared the effects
of placebo, atomoxetine 20, 45, or 90 mg and methylphenidate
20 or 40 mg on subjective, physiologic, and psychomotor
measures.[27] Results demonstrated that atomoxetine did not
significantly differ from placebo in perceptions of stimulant
and euphoric effects, but methylphenidate was associated with
significantly higher perceptions of these effects than placebo
(p < 0.05). Atomoxetine 90 mg was associated with bad and
sick feelings, differing significantly from placebo in these
measures (p < 0.05).[27] Data from a study involving six healthy
volunteers with a recent history of nontherapeutic stimulant
abuse who received methylphenidate 530 mg, atomoxetine
1590 mg, dexamfetamine 2.515 mg, triazolam 0.060.375 mg,
and placebo suggest that, while behavioral effects of atomoxetine overlap somewhat with psychomotor stimulants, it has a
low abuse potential.[28] This conclusion is potentially supported
by the lack of extracellular increase of dopamine in the nucleus
accumbens and striatum (section 2.1).[16]
Atomoxetine recipients demonstrated an initial loss in both
expected weight and height, although these shortfalls peaked at
15 and 18 months, respectively, and returned to expected measurements by 36 and 24 months, according to the interim results of a
long-term, open-label extension study.[29] Persistent decreases from
the expected measurements appeared to occur in patients who
were taller or heavier than average before treatment.[29] The
study involved pediatric patients (n = 1312; 5-year data n = 61)
who were enrolled in one of 13 clinical atomoxetine trials and
who subsequently received long-term atomoxetine treatment.
207
Sexual development did not appear to be affected by atomoxetine treatment in an analysis (available as an abstract) of
15 months treatment with atomoxetine compared with placebo in
children and adolescents with ADHD using Tanner staging.[30]
Children with ADHD receiving atomoxetine 11.8 mg/kg/day
had a smaller increase in sleep-onset latencies than those receiving
methylphenidate 0.91.8 mg/kg/day (12.06 vs 39.24 minutes;
p < 0.001), according to results from a randomized, double-blind,
crossover study.[31] Other actigraphy measures demonstrated that
atomoxetine recipients worsened to a significantly lesser extent
than methylphenidate recipients, with regard to total sleep interval
(p = 0.004) and assumed sleep time (p = 0.016), although methylphenidate recipients showed an improved interrupted sleep time
compared with a worsened interrupted sleep time among atomoxetine recipients (p = 0.025), as well as the number of sleep interruptions worsening to a significantly (p = 0.011) greater extent among
atomoxetine recipients than among methylphenidate recipients.[31]
When monoamine oxidase inhibitors (MAOIs) have been
administered concomitantly with other drugs that affect brain
monoamine concentrations, reports of serious, sometimes fatal,
reactions have occurred. Thus, coadministration of atomoxetine and MAOIs is contraindicated.[10,11] Other drugs that
interact with atomoxetine include pressor agents (e.g. dopamine), with subsequent effects on blood pressure, and highdose nebulized[11] or systemically administered[10,11] b2-agonists
(e.g. albuterol [salbutamol]), with possible effects on heart rate
and blood pressure.[10,11] Atomoxetine should therefore be
coadministered with caution with pressor agents or b2-agonists.
Atomoxetine made no difference to the intoxicating effects of
ethanol or the cardiovascular effects of methylphenidate.[10]
The UK prescribing information states that atomoxetine
should also be used with caution with drugs that affect norepinephrine levels (such as antidepressants or certain decongestants), as there is a potential for additive or synergistic effects;
caution is also advised with drugs that lower the seizure threshold
(e.g. antidepressants, antipsychotics), as there is a potential risk of
seizures with atomoxetine.[11] When atomoxetine is administered
with QT-prolonging drugs (e.g. antipsychotics or class IA and III
antiarrhythmics), drugs that cause an imbalance in electrolytes
(e.g. thiazide diuretics), or drugs that inhibit cytochrome P450
(CYP) 2D6, there is a potential for an increased risk of QT prolongation, according to the UK prescribing information.[11] These
precautions are not specified in the US prescribing information.[10]
3. Pharmacokinetic Properties
This section focuses, where possible, on results from an openlabel pharmacokinetic study conducted in children and adolescents
208
aged 714 years with a DSM-IV diagnosis of ADHD who

received either a single 10 mg dose of oral atomoxetine (n = 7)
or atomoxetine 2045 mg twice daily for 11 weeks (n = 16)
[dosage was not adjusted for weight].[32] Most doses were not
administered within 1 hour of a meal. Although it was not a
requirement, all patients were extensive metabolizers of
CYP2D6 substrates (extensive metabolizers). The vast majority
of the general population are extensive metabolizers, with 7% of
Caucasians and 2% of African-Americans being poor metabolizers of CYP2D6 substrates (poor metabolizers);[10] some
pharmacokinetic data are available for pediatric poor metabolizers.[33] Dosage adjustments are recommended in the poor
metabolizer population (section 7).
Atomoxetine pharmacokinetics have been demonstrated to
be similar for adults and children or adolescents, once weight is
adjusted for.[32] Therefore, some data presented in this section
are from studies in adult subjects, when no pediatric data are
available. These data were obtained from a review article[34] and
from the US prescribing information.[10]
While there are few published pediatric data for poor metabolizers, it has been demonstrated in adult poor metabolizers
that values for the area under the plasma concentration-time
curve (AUC) and maximum plasma concentration (Cmax) are
10- and 50-fold higher than in extensive metabolizers, and that
atomoxetine elimination is slower, with a plasma half-life (t1=2 )
of 24 hours.[10]
A population pharmacokinetic, one-compartment model
was constructed, using data from five studies in pediatric patients receiving dosages of atomoxetine 1090 mg/day, administered twice daily.[33] This model demonstrated that drug
clearance among pediatric poor metabolizers is 9-fold lower
than that among extensive metabolizers.
3.1 Absorption and Distribution
Oral atomoxetine is rapidly absorbed; Cmax (144 ng/mL) was

reached in 2 hours among children and adolescents with
ADHD (all of whom were extensive metabolizers) receiving a
single dose of atomoxetine 10 mg.[32] The AUC from time zero
to infinity (AUC1) was 645 ng h/mL.
Corresponding data for children and adolescents with ADHD
receiving multiple doses of 4090 mg/day are 537 ng/mL (Cmax at
steady state), 1.73 hours, and 2250 ng h/mL.[32]
Adult studies demonstrated an absolute oral bioavailability of
63% in extensive metabolizers and 94% in poor metabolizers.[10]
Atomoxetine demonstrated dose-proportional increases in plasma exposure.[32] When administered with food, atomoxetine was
absorbed at a slower rate, with a 9% lower Cmax in children and
adolescents; however, atomoxetine may be administered with or

without food.[10] The steady-state volume of distribution
(2.25 L/kg[32]) indicates that atomoxetine primarily distributes
into total body water.[10] Plasma protein binding (mainly to albumin) of atomoxetine was 98% at therapeutic concentrations.[10]
3.2 Metabolism and Elimination
Atomoxetine undergoes extensive biotransformation.[10] In

extensive metabolizers, it is mainly metabolized via the CYP2D6
enzymatic pathway, in which atomoxetine is oxidated to form
4-hydroxyatomoxetine (the major metabolite), which is then
glucuronidated to form 4-hydroxyatomoxetine-O-glucuronide,
the main excreted metabolite (accounting for >80% and <17% of
the total dose in urine and feces); <3% of the total atomoxetine
dose is excreted as unchanged drug.[10,34] Poor metabolizers are
unable to metabolize as efficiently using the CYP2D6 pathway;
metabolism in these individuals occurs mainly via the CYP2C19
pathway, forming N-desmethylatomoxetine.[10,34] Several other
CYP isoforms are able to form 4-hydroxyatomoxetine and
N-desmethylatomoxetine; thus, 4-hydroxyatomoxetine is still the
most common metabolite, even in poor metabolizers.[10,34]
4-Hydroxyatomoxetine has similar pharmacologic activity to
atomoxetine (although, unlike atomoxetine, it does have relatively high affinity for the human serotonin transporter),[34] but
circulates in plasma at lower concentrations (e.g. at 1% of atomoxetine concentrations in extensive metabolizers).[10] Conversely, N-desmethylatomoxetine has much less pharmacologic
activity than atomoxetine and 4-hydroxyatomoxetine,[34] but also
circulates at lower concentrations.[10]
Atomoxetine has a short half-life (just over 3 hours); this
explains the low amount of atomoxetine accumulation (mean
9% in pediatric patients) observed at steady state.[32]
Time-invariant pharmacokinetics were indicated by the pediatric study; t1=2 , apparent clearance, and apparent volume of
distribution were all similar after a single dose (3.12 hours,
0.455 L/h/kg, and 1.96 L/kg, respectively) and at steady state
(3.28 hours, 0.477 L/h/kg, and 2.25 L/kg).[32]
3.3 Special Populations
Extensive metabolizers with moderate (Child-Pugh class B)

or severe (Child-Pugh class C) hepatic insufficiency have increased atomoxetine exposure compared with healthy volunteers.[10] Therefore, dosage reduction is recommended in these
patients (section 7).[10,11] Following a single dose of atomoxetine 20 mg, AUC1 was significantly higher in adults with
moderate (n = 6) or severe (n = 4) hepatic impairment than in
healthy volunteers (1.59 vs 0.85 mg h/mL; p < 0.05).[35]
Extensive metabolizers with end-stage renal disease showed no

significant difference from healthy volunteers when exposure was
corrected for dosage.[10] Atomoxetine pharmacokinetics were not
influenced by sex or ethnic origin (other than Caucasians having a
higher likelihood of being poor metabolizers).[10]
3.4 Drug Interactions
Atomoxetine was not associated with clinically important inhibition or induction of CYP isoenzymes, including CYP1A2,
CYP3A, CYP2D6, and CYP2C9.[10] No dosage adjustment is
considered necessary for drugs metabolized by CYP3A or
CYP2D6.[10]
Healthy extensive metabolizers receiving both atomoxetine
20 mg twice daily and paroxetine 20 mg once daily, a potent
CYP2D6 inhibitor, demonstrated pharmacokinetic parameters
for atomoxetine that were similar to those seen among poor metabolizers.[36] Coadministration of paroxetine with atomoxetine
was associated with 3.5-, 6.5-, and 2.5-fold increases in atomoxetine steady-state Cmax, AUC from time 1 to 12 hours, and t1=2 ,
respectively.[36] Dosage adjustment is recommended for pediatric
patients receiving potent CYP2D6 inhibitors (see section 7).[10] In
vitro studies suggest that CYP2D6 inhibitors have no effect on
atomoxetine pharmacokinetics among poor metabolizers.[10]
Atomoxetine had no effect on the binding of warfarin, aspirin
(acetylsalicylic acid), phenytoin, or diazepam to human albumin,
or vice versa, according to results from in vitro drug-displacement
studies.[10] Gastric pH-elevating drugs (e.g. antacids, omeprazole)
had no effect on the bioavailability of atomoxetine.[10]
4. Therapeutic Efficacy
The focus of this section is on data from large (n >100), fully
published, randomized, controlled trials investigating the efficacy
of atomoxetine in children and adolescents with ADHD. It
should be noted that the vast majority of atomoxetine clinical
trials included dosages that were potentially higher than the
maximum approved dosage of 1.4 mg/kg/day or 100 mg/day. For
definitions of some of the rating scale abbreviations and descriptions of rating scales referred to in this section, see table I.
4.1 Comparisons with Placebo
The efficacy of oral atomoxetine was compared with that of

placebo in the treatment of children and adolescents with ADHD
in eight 6- to 9-week, randomized, double-blind, multicenter,
short-term, fully published trials;[37-43,58] one multinational
study with two randomized, double-blind, placebo-controlled
phases has investigated longer term results.[46,47] Two randomized, double-blind, multicenter trials of 10[59] and 12[60] weeks
209
duration investigated the efficacy of atomoxetine versus placebo

in a stimulant-naive population.
4.1.1 Short-Term Treatment
Patients in the short-term trials were randomized to receive

once-[38,40-43] or twice-daily[37,39] atomoxetine or placebo. One fixeddose trial titrated patients to a target dosage of atomoxetine 0.5, 1.2
or 1.8 mg/kg/day.[37] Three other trials titrated patients to a target
dosage of atomoxetine 1.0[38] or 1.2[42,43] mg/kg/day, although the
dosage could be further increased to 1.5[38] or 1.8[42,43] mg/kg/day if
required. The remaining four trials titrated patients according to
therapeutic response; permitted atomoxetine dosages were
0.81.8,[41] 1.8,[40] or 2[39] mg/kg/day. Where specified, final mean
atomoxetine dosages were 1.3,[38,41-43] 1.4,[40] and 1.5[39] mg/kg/day.
Eligible patients aged 618 years in the short-term trials had a
DSM-IV diagnosis of ADHD, as confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age
Children-Present and Lifetime version (K-SADS-PL),[37,38,41-43]
the K-SADS-Epidemiologic version (K-SADS-E; Chinese version),[40] or an unspecified version of K-SADS.[39] Most patients
were required to have a minimum ADHD-RS total score of 25 for
boys and 22 for girls (or 12 for the inattentive or hyperactive/
impulsive score),[40] or ADHD-RS total or inattentive or hyperactive/impulsive subscale scores 1[42] or 1.5[37-39,43] SD above age
and sex norms. Exclusion criteria included below-average intelligence levels,[37,39-42] use of other psychotropic medication,[37-43]
weight <25[39,41] or <20[40] kg or >60[40] kg, or a history of or current psychosis,[37-41,43] bipolar disorder,[37-41,43] or serious medical
illness.[37,38,40,42,43] Two trials also excluded patients who were
poor metabolizers.[39]
The primary endpoint for all short-term placebo-controlled
trials was the change in the investigator-administered ADHD-RS
total score (parent[37-40,43] or teacher[41,42] version) from baseline
to endpoint.
Additional endpoints included scores on the inattentive and
hyperactive/impulsive subscales of the ADHD-RS,[37-40,42,43] response rate (see table II for definitions of response),[38,39,41-43] and
CPRS,[37-42] CTRS,[38,40] CGI-ADHD-S,[39,40,43] and CGI-S[37,38,42]
scores; as well as health-related quality of life (HR-QOL), rated on
the CHQ psychosocial summary score.[37,41] Two studies[38,43]
specifically investigated morning and evening efficacy using
the DPREMB, both original[38] and revised (DPREMB-R)[43]
versions.
The majority of patients in treatment groups were diagnosed
with the combined subtype (5581%); inattentive and hyperactive/
impulsive subtype proportions ranged from 19% to 41% and from
0% to 4%, respectively.[37-43] The mean patient age ranged from
9.1 to 11.5 years.[37-43] The majority of patients were male
210
Table I. Definition of efficacy rating scale abbreviations and description of rating scales used in clinical studies[23-26,37-57]
Rating scale
Range
Description
ADHD-Rating Scale (ADHD-RS)
054
18-item rating scale, each item corresponding to a symptom contained in the DSM-IV
ADHD diagnosis. Each item is scored from 0 (never or rarely) to 3 (very often). It
includes the subscales inattentive and hyperactive/impulsive. Parent and teacher
versions are both available
Child Health and Illness Profile-Child,

Adolescent or Parental Edition (CHIP-CE,
CHIP-AE or CHIP-PRF)
NA
76-item parent- or patient-rated quality-of-life rating scale. The total score is the mean
score of the five domains (satisfaction, comfort, resilience, risk avoidance, and
achievement), which is then standardized to a t-score (a mean SD of 50 10, based
on norms of a sample of US children). A higher score implies a higher quality of life
Childrens Health Questionnaire (CHQ)
0100
50-item parent-rated quality-of-life rating scale, measuring 14 physical and

psychosocial concepts. A higher score implies a higher quality of life
Clinical Global Impressions-Improvement

scale (CGI-I)
17
7-point scale for rating the improvement of mental illness, taking into account the total
clinical experience. Rating is from 1 (very much improved), through to 4 (no change), to
7 (very much worsened)
Clinical Global Impressions-ADHD-Severity

scale (CGI-ADHD-S)
17
7-point scale for rating the severity of ADHD, taking into account the total clinical
experience. Rating is from 1 (normal) to 7 (extremely ill)
Clinical Global Impressions-Severity scale

(CGI-S)
17
7-point scale for rating the severity of mental illness, taking into account the total clinical
experience. Rating is from 1 (normal) to 7 (extremely ill)
Conners Parent/Teacher Rating Scale

(CPRS/CTRS)
03 per item
Parent- or teacher-rated ADHD rating scale with direct links to the DSM-IV. Each item is
scored from 0 (never) to 3 (very often). Studies varied in the number of items included in
their analyses
Daily Parent Ratings of Evening and

Morning Behavior scale (DPREMB)
052
13-item parent-completed questionnaire, examining behavior in the morning and

evening. Each item is scored from 0 (not present) to 4 (extremely problematic)
Daily Parent Ratings of Evening and

Morning Behavior-Revised scale
(DPREMB-R)
033
11-item parent-completed questionnaire, examining behavior in the morning (3 items)

and evening (8 items). Revised version of the DPREMB. Each item is scored from
0 (no difficulty) to 3 (a lot of difficulty)
Pediatric Quality of Life Inventory (PedsQL)
0100
4-subscale quality-of-life rating scale. A higher score implies a higher quality of life
Swanson, Kotkin, Agler, M-Flynn, and

Pelham behavioral rating scale (SKAMP)
06 per item
13-item rating scale representing classroom behavior (6 deportment items, 7 attention

items). Each item is scored from 0 (normal) to 6 (maximum impairment). The deportment and
attention subscale scores are acquired by calculating the mean of the items in each scale
Swanson, Nolan, and Pelham Rating

Scale-Revised (SNAP-IV)
03 per item
26-item rating scale (18 items for ADHD symptoms, 9 items for ODD symptoms). Each
item is scored from 0 (not at all) to 3 (very much). Scores are yielded in three domains:
inattention, hyperactivity/impulsivity, and oppositional
ADHD = attention-deficit hyperactivity disorder; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; NA = not applicable;
ODD = oppositional defiant disorder.
(7090%),[37-43] and 4861% had received previous stimulant

treatment.[38,40-43]
The most common (10% of patients) co-morbid disorders
included ODD,[37-43] learning disorders,[41,42] elimination disorders,[39] and phobias.[39]
Assessments were based on the modified intention-to-treat
(mITT) population[37-43] using last-observation-carried-forward (LOCF) imputation.[37-41,43] Between-group differences
in baseline characteristics within each trial were not significant,
except for in a combined analysis of two studies,[39] which
showed a significantly (p < 0.05) higher mean Wechsler Intelligence Scale Intelligence Quotient (WISC-IQ) score among
placebo than atomoxetine recipients; this was shown to have no

effect on the efficacy conclusions.
Once- or twice-daily atomoxetine was effective in the shortterm treatment of ADHD in children and adolescents (table II).
The mean improvement from baseline in ADHD-RS total score
(primary endpoint) was significantly greater among atomoxetine than placebo recipients in all eight short-term trials
(reduction of 10.317.3 vs 5.09.3; all p < 0.05)[37-43] [table II].
In addition, results from the trials reporting inattentive and
hyperactive/impulsive subscale scores[37-40,42,43] demonstrated
that these scores also improved to a significantly greater extent
after atomoxetine versus placebo administration (table II). Of the
211
six trials reporting response rates, five[38,39,41,43] reported significantly higher response rates among atomoxetine than placebo
recipients (5960% vs 2540%; all p < 0.05); the remaining trial[42]
reported no significant difference (69% vs 43%) [table II].
The two studies investigating HR-QOL, rated on the CHQ
psychosocial summary score, reported differing results. One
study[41] reported no significant difference between atomoxetine
and placebo recipients in the change from baseline in the CHQ
psychosocial summary score (+7.1 vs +3.7; baseline scores of 32.5
and 32.1). The other study[37] reported significant differences
between patients receiving any of the three dosages of atomoxetine (0.5, 1.2, and 1.8 mg/kg/day) and placebo recipients for the
change from baseline in the CHQ psychosocial summary score
(+4.4, +6.0, and +9.1 vs -0.9; all p < 0.05 vs placebo) [baseline
scores of 32.9, 35.4, 31.3, and 35.2, respectively].
Other efficacy measures, including CPRS,[37-42] CTRS,[38,40]
CGI-S,[38,42] and CGI-ADHD-S[39,40,43] scores, were also significantly
(p < 0.05) improved among atomoxetine versus placebo recipients.
Two studies specifically investigating evening efficacy of a
single morning dose of atomoxetine found that it had a positive
Table II. Efficacy of oral atomoxetine (ATO) in the short-term treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD).
Results from eight randomized, double-blind, placebo (PL)-controlled, multicenter trials in patients (pts) aged 618 years.[37-43] The primary endpoint in all
studies was the ADHD-Rating Scale (ADHD-RS) total score
Study
Treatment
duration
(wk)
Age of pts Treatmenta

(y)
(mg/kg/day)
Brown et al.[41]
812
Gau et al.
[40]
616
Kelsey et al.[43]
612
Michelson et al.[37]f
818
Michelson et al.
616
Spencer et al.
712
(Study 1)
PL
51
64.4e
-5.0e
69
36.7
-17.3**
-8.7*
ATO 1.8
Spencer et al.
712
812
(Study 2)
Weiss et al.[42]
Responsec rate
(% pts)
66**
65.6e
36
-8.7***
29
37.1
-9.3
-5.2
-4.1
126
42.1
-16.7*
-8.3*
-8.5*
63***
PL
60
42.3
-7.0
-4.1
-2.9
33
ATO 1.2d
84
39.2
-13.6*
-7.0*
-6.6*
ATO 1.8d
82
39.7
-13.5*
-6.8*
-6.7*
PL
83
38.3
-5.8
-2.5
-3.2
ATO 1.2d
ATO 1.0
ATO 2.0
PL
[39]g
-10.3***e
99
PL
[39]g
Mean ADHD- Mean change from baseline in

RSb total score ADHD-RSb score
at baseline
total
inattentive hyperactive/
impulsive
ATO 0.81.8d
PL
[38]
No. of pts
ATO 2.0
PL
ATO 1.2d
PL
***
84
37.6
-12.8
-7.1
83
36.7
-5.0
-2.9
***
64
41.2
-15.6
-7.5
61
41.4
-5.5
-3.0
63
37.8
60
37.6
100
38.9
51
36.7
***
-14.4
-5.9
-14.5***
-7.2
-7.6
***
***
***
-5.7***
60***
-2.1
31
***
-8.0
64***
-2.5
25
**
59*
-6.9
-3.0
-2.9
40
-7.5*
-7.0***
69
-4.3
-3.0
43
a Treatment was administered either once daily in the morning[38,40-43] or in divided doses twice daily, in the morning and early evening.[37,39]
b Investigator-administered parent[37-40,43] or teacher[41,42] version.
c Defined as 25% reduction from baseline in ADHD-RS total score;[38,39,43] an endpoint t-score using chi-square analyses that was no worse than 1 SD below
age and sex norms;[41] or 20% reduction from baseline in ADHD-RS total score.[42]
d Of the four fixed-dose trials, one titrated patients to a target dosage of ATO 0.5, 1.2, or 1.8 mg/kg/day,[37] and three titrated patients to a target dosage of
ATO 1.0[38] or 1.2[42,43] mg/kg/day, although the dosage could be further increased to 1.5[38] or 1.8[42,43] mg/kg/day if required. The remaining four trials
titrated patients according to therapeutic response; permitted ATO dosages were 0.81.8,[41] 1.8,[40] or 2[39] mg/kg/day.
e The ADHD-RS total score was standardized to a t-score (a mean SD of 50 10, based on norms of a sample of children) in this study.
f An additional ATO treatment group (ATO 0.5 mg/kg/day) was included, but results have not been reported as this group was only present to show any dosedependent effect and was not included in the primary analysis.
g Methylphenidate treatment group was included as a positive control, but the data are not reported.
*
p < 0.05, ** p < 0.01, *** p 0.001 vs PL.
212
effect compared with placebo. One study[43] reported significant

improvement on an overall evening parent-rated scale (p < 0.05 vs
placebo), as well as on five of the eight evening subscale scores
(all p < 0.05 vs placebo). The other study[38] reported significant
improvement on two of the nine evening items (both p < 0.05 vs
placebo), but did not report an overall evening result.
Of the six trials[37,38,40-43] that did not exclude poor metabolizers, only one reported efficacy results in this population.[37] However, a pooled analysis of four randomized,
double-blind studies[37-39] reported that significantly (p = 0.002)
greater reductions from baseline in mean ADHD-RS-IV total
scores were observed among poor metabolizers (-20.9; n = 30)
than among extensive metabolizers (-14.1; n = 559).[61] Baseline
mean ADHD-RS-IV total scores were 38.9 and 40.3 in this
pooled analysis. Response rates (percentage of patients with a
25% decrease from baseline in ADHD-RS-IV total score)
were also significantly higher among poor metabolizers than
among extensive metabolizers (80% vs 59%; p = 0.033).
Atomoxetine efficacy does not appear to differ between
children and adolescents, but it does appear more effective
among older children than younger children. A meta-analysis
of six trials, involving children aged 611 years (n = 510 atomoxetine, n = 341 placebo) and adolescents aged 1217 years
(n = 107 atomoxetine, n = 69 placebo) receiving atomoxetine or
placebo for 68 weeks, revealed no significant differences in the
effects on ADHD symptoms (rated on the ADHD-RS, the
CGI-S, and the CPRS), response rates, or time to response.[44]
Another meta-analysis of six 6- to 9-week trials compared
atomoxetine efficacy versus placebo among young children
(67 years; n = 184 atomoxetine, n = 96 placebo) versus older
children (812 years; n = 544 atomoxetine, n = 316 placebo).[62]
It found that, while both age groups showed a significantly
greater improvement in ADHD-RS scores and response rates
among atomoxetine versus placebo recipients (p < 0.05), older
children had significantly (p < 0.05) greater improvements in
ADHD-RS scores than younger children, regardless of whether
they were receiving atomoxetine or placebo.[62]
Discontinuation of atomoxetine does not appear to be associated with symptom rebound. A prospective pooled analysis
of two 9-week randomized, double-blind, placebo-controlled
trials involving a total of 194 (102 atomoxetine 2 mg/kg/day
and 92 placebo recipients) children aged 712 years with
ADHD was carried out.[45] The trial demonstrated that among
patients originally administered atomoxetine, ADHD-RS total
scores, while worsening on treatment discontinuation (p < 0.001
vs original placebo recipients), did not return to pretreatment
levels after a 1-week discontinuation phase, during which all
patients received placebo in a single-blind manner.
4.1.2 Longer Term Treatment
A multicenter study has investigated longer term atomoxetine

administration in this population. This study was in two phases:
the first[47] investigated 9-month relapse prevention in responders
(response defined as a decrease of 25% in ADHD-RS total score
and a CGI-S score of 1 or 2) to an initial 12-week period of openlabel atomoxetine treatment; the second[46] was a re-randomized
6-month extension phase in recipients of atomoxetine in the first
phase. Patients were aged 615 years and had a DSM-IV diagnosis
of ADHD confirmed by K-SADS-PL, and a symptom severity of
1.5 SD above US age and sex norms. Exclusion criteria included
bipolar or psychotic disorders, unstable medical illness, and concomitant psychotropic medication (other than atomoxetine).
The primary endpoint for both phases was time to relapse
(defined as an increase in ADHD-RS total score to 90% of the
baseline score plus an increase in CGI-S score by 2
points).[46,47] Additional endpoints included relapse rate[46,47]
and ADHD-RS total,[46,47] CGI-S,[47] CHQ,[46,47] CPRS,[46,47]
and CTRS[46,47] scores.
Of the 604 patients who entered the initial 12-week atomoxetine treatment period (target dosage 1.2 mg/kg/day [as two equal
doses in the morning and evening], maximum 1.8 mg/kg/day),
416 responded to treatment and were randomized in a doubleblind manner to 9 months of atomoxetine (at the same dosage;
n = 292) or placebo (n = 124) treatment. Of the atomoxetine recipients, 163 were re-randomized to a further 6 months of atomoxetine (n = 81) or placebo (n = 82) treatment. The mean final
atomoxetine dosages were 1.56 mg/kg/day for the 9-month period
and 1.55 mg/kg/day for the subsequent 6-month period.[46,47]
The only common (10% of patients) co-morbid disorder in
this study was ODD. The mean patient age ranged from 10.1 to
11.0 years, and 8990% of patients were male.[46,47] Combined
and inattentive subtype proportions in treatment groups ranged from 73% to 74% and from 21% to 23%; 5% of patients were
hyperactive/impulsive.[46,47] A total of 5054% of patients in
one phase had previously received stimulant therapy.[47]
Assessments were based on the mITT population using
LOCF imputation. Between-group differences in baseline
characteristics within each phase were not significant.
Atomoxetine was effective in the longer term treatment of
ADHD in children and adolescents. Among responders, atomoxetine was associated with a significantly longer mean time to
relapse than placebo in both the 9-month (217.7 vs 146.1 days;
p < 0.001)[47] and 6-month (160.5 vs 130.8 days; p = 0.008)[46]
periods. Relapse rates for atomoxetine and placebo recipients
were 22% and 38% (p < 0.01)[47] in the 9-month, and 3% and 12%
(relative risk ratio for relapse with placebo vs atomoxetine 5.6;
95% CI 1.2, 25.6)[46] in the 6-month periods.
Mean total ADHD scores increased to a significantly smaller

extent among atomoxetine compared with placebo recipients in
both periods (9-month: +6.8 vs +12.3, p < 0.001; 6-month: +1.7 vs
+7.8, p < 0.001); mean inattentive and hyperactive/impulsive
symptom scores also increased to a significantly smaller extent
among atomoxetine versus placebo recipients (all p < 0.01).[46,47]
Other efficacy endpoints revealed differing results in the two
phases. In the first,[47] both CGI-S and CPRS scores increased to a
significantly (p < 0.05) lesser extent among atomoxetine versus
placebo recipients; however, the change in CTRS scores did not
significantly differ between treatment groups. In the second phase,
however, CTRS score improved to a significantly greater extent
among atomoxetine than placebo recipients, and CPRS score
changes did not significantly differ between treatment groups.[46]
Atomoxetine recipients demonstrated a significantly smaller
decline in HR-QOL compared with placebo recipients, as
assessed by mean CHQ psychosocial summary scores, in the
9-month (-5.6 vs -9.5; p = 0.016)[47] but not the 6-month (-0.9
vs -2.9)[46] period.
Atomoxetine appears to maintain efficacy for at least 2 years
with no evidence of drug tolerance. Two meta-analyses of 13
trials each, one in 219 adolescents (aged 1218 years)[49] and one
in 97 young children (aged 67 years)[48] with ADHD who were
treated with atomoxetine for a minimum of 2 years, showed
that atomoxetine retained significant (p < 0.001) improvement
at endpoint versus baseline in ADHD-RS scores.[48,49] Dosage
escalation was not required.[49]
4.1.3 In Stimulant-Naive Patients
Two randomized, double-blind, placebo-controlled, multicenter trials have investigated the efficacy of atomoxetine in
stimulant-naive patients aged 615[60] or 715[59] years with a
K-SADS-PL-confirmed DSM-IV diagnosis of ADHD.[59,60]
Some additional efficacy data for the 12-week study[60] were taken
from an abstract.[63] Patients were randomized to treatment with
atomoxetine (n = 49[59] and 99[60]) or placebo (n = 50[59,60] ) for
10[59] or 12[60] weeks. The atomoxetine dosage, taken in the morning, was 0.5 mg/kg/day (40 mg/kg in patients weighing >70 kg[59])
for the first 1[59] or 2[60] weeks and increased to a target[60] dosage
of 1.2 mg/kg/day (80 mg/day in patients weighing >70 kg[59]) for
the rest of the treatment period.[59,60]
Eligible patients had an ADHD-RS total score of 1.5 standard deviations above the US[59] age[59,60] and sex[59] norms for
their diagnostic subtype, were stimulant-naive,[59,60] and were
newly diagnosed.[60] Exclusion criteria included impaired intellect;[59,60] serious medical illness;[59] a history of psychosis,[59,60]
bipolar disorder[59,60] or pervasive developmental disorder;[60]
alcohol or drug abuse[59,60] within the past 3 months;[59] use of
213
psychoactive medication;[59,60] a need for immediate pharmacotherapy;[59] and psychotherapy.[59,60]

Primary endpoints were the change from baseline in total
ADHD-RS score[60] and HR-QOL, rated on the CHIP-CE
achievement domain (primary endpoint data not available from
this study).[59] Other endpoints included ADHD-RS total,[59]
inattention,[59,60] and hyperactivity/impulsivity[59,60] scores,
CGI-S[59] or CGI-ADHD-S[60] scores, CGI-I scores,[59] response
rates (the proportions of patients with a 25% or 40% improvement from baseline in ADHD-RS total score),[59] and
CHIP-CE, -AE and -PRF.[60]
Most patients in both studies were male (81%[59] and 80%[60]),
with a mean age of 12[59] or 10[60] years. A total of 78%[59] and
63%[60] had the combined ADHD subtype; 4%[59,60] had the hyperactive subtype, and 18%[59] and 33%[60] had the inattentive subtype. The most common co-morbid disorder was ODD (20%[59]
and 26%[60]); other common (10% of patients) co-morbidities
included tics (14%[59] and 17%[60]) and anxiety disorders (13%[60]).
Assessments were based on the mITT population,[59,60] using
LOCF imputation.[59] No differences were reported between
groups in baseline characteristics.[59,60]
Atomoxetine was effective in stimulant-naive pediatric patients with ADHD. ADHD-RS total scores decreased to a
significantly (p < 0.001)[59,63] greater extent with atomoxetine
than with placebo (-19.0 vs -6.3[59] and -12.8 vs -4.7[60]);
baseline scores in atomoxetine and placebo recipients were 38.9
and 39.5[59] and 39.1 and 39.5.[60]
Atomoxetine was associated with an increased efficacy related to a longer treatment duration. After 12 weeks, the
ADHD-RS total score was significantly improved compared
with after 6 weeks of atomoxetine treatment (p = 0.0132).[63]
Where reported,[59] other endpoints support the efficacy of
atomoxetine. ADHD-RS inattention and hyperactivity/
impulsivity subscale scores, as well as CGI-S and -I scores, were all
significantly (p < 0.001) improved among atomoxetine versus placebo recipients.[59] Significantly (p < 0.001) more atomoxetine than
placebo recipients had a 25% (71% vs 29%) or 40% (63% vs
14%) improvement in ADHD-RS total scores.[59]
HR-QOL was significantly improved with regard to risk avoidance and achievement among atomoxetine versus placebo recipients; no significant difference was noted between treatment groups
in the other three domains (satisfaction, comfort, and resilience).[60]
When rated on the CHIP-PRF, risk avoidance and achievement
improved to a greater extent with atomoxetine than with placebo
(+7.89 vs -0.64 [p < 0.001] and +4.94 vs +1.55 [p = 0.042]); baseline scores were 31.7 and 34.1 for risk avoidance and 33.2 and
33.1 for achievement.[60] When rated on the CHIP-CE/AE
(combined), risk avoidance again improved to a greater extent
214
Table III. Efficacy of atomoxetine (ATO) vs other attention-deficit hyperactivity disorder (ADHD) medication in the treatment of children and adolescents with
ADHD. Results from six randomized, open-label[25,50,51] or double-blind,[23,24,26] multicenter trials comparing the efficacy of ATO with immediate-release
methylphenidate (MPH),[24,25] osmotically released MPH (OR MPH),[23,51] extended-release mixed amfetamine salts (MAS)[26] or standard current therapy
(SCT)[50] in patients (pts) aged 616 years
Study
Treatment
duration
(wk)
[51]
Kemner et al.
Age of pts
(y)
612
(FOCUS)
[25]
Kratochvil et al.
Newcorn et al.
10
[23]
Treatmenta
No.
of
pts
10
Wigal et al.[26]
baseline endpoint
baseline change
ATO
850
38.6
-16.0
69
473
39.9
-20.2**e
80**
ATO 2 mg/kg/day
178
39.4
-19.4
79 (girls)
MPH 560 mg/day
40
37.6
-17.8e
616
ATO 0.81.8 mg/kg/day
222
40.9
-14.4
45ze
OR MPH 1854 mg/day
220
40.0
-16.9*
56*zzg,e
74
41.7
-7.3
104
45.5
23.5-h
715

SCT
baseline change
Response
ratec
(% pts)
OR MPHd
Mean SKAMP
deportment score
715 (boys)
(SUNBEAM)
Wang et al.[24]
Mean CHIP-CE
total t-score
PL
Prasad et al.[50]
Mean ADHD-RSb
total score
616
612
(StART)
24e
23.2
79-/65-i
48/35i
97
45.6
33.7
162
38.6
-21.1
77e,k
MPH 0.20.6 mg/kg/day
164
37.4
-21.6
82e
101
MAS 1030 mg/day
23.9
38.4-e
30.8
1.63
102
1.44
-0.13e
**e
-0.56
38/28l
70**/68**l
a ATO was administered either once daily,[24,26,51] in divided doses twice daily,[23,25] or one or the other.[50] MPH was administered either twice daily[24] or one
of once, twice or three times daily.[25] OR MPH and MAS were both administered once daily.[23,26,51]
b Studies used an investigator-administered version of the parent[24,25] or an unspecified[23,50,51] version of ADHD-RS.
c Defined as a 25%[50,51] and/or 40%[23,24,50] reduction from baseline in ADHD-RS total score; or a 25% improvement on the SKAMP deportment or
attention scales.[26]
d Dosage was individually tailored to simulate clinical practice, on the basis of clinical judgment and the US FDA-approved prescribing information.
e Primary endpoint.
f Cytochrome P450 2D6 poor metabolizers received ATO 0.21.0 mg/kg/day.
g ATO did not demonstrate noninferiority to OR MPH.
h Presented as value at endpoint, not change from baseline.
i Data presented as 25%/40% response rate.
j SCT included any combination of medicines (excluding atomoxetine) and/or behavioral counseling, or no treatment.
k ATO was noninferior to MPH.
l SKAMP deportment/attention scale response rate.
ADHD-RS = ADHD-Rating Scale; CHIP-CE = Child Health and Illness Profile-Child Edition; FOCUS = Formal Observation of Concerta versUs Strattera;
PL = placebo; SKAMP = Swanson, Nolan, and Pelham Rating Scale; StART = Strattera/Adderall Randomized Trial; SUNBEAM = Study into the broader
efficacy of atomoxetine; * p < 0.05, ** p < 0.001 vs ATO; - p < 0.001 vs SCT; z p = 0.003, zz p 0.001 vs placebo.
with atomoxetine than with placebo (+3.60 vs +0.03; p = 0.006)

from baseline scores of 47.6 and 49.1; however, no significant
treatment difference was noted for achievement on this scale.[60]
4.2 Comparisons with Stimulants or Standard
Current Therapy
The efficacy of oral atomoxetine compared with other ADHD

medication in the treatment of children and adolescents aged
616 years with ADHD has been evaluated in six randomized,

open-label[25,50,51] or double-blind,[23,24,26] multicenter, fully published trials lasting 310 weeks (table III).[23-26,50,51] Active comparators included immediate-release methylphenidate,[24,25]
osmotically released methylphenidate,[23,51] extended-release
mixed amfetamine salts (this study was conducted in a laboratory
school setting),[26] and standard current therapy (any combination
of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment).[50] It should be noted that two of these trials
(comparing atomoxetine with extended-release mixed amfetamine

salts[26] and osmotically released methylphenidate[51]) were of only
3 weeks duration; full benefits of atomoxetine often take several
weeks (potentially up to 8 weeks)[8] to occur.[2,64] Additionally, one
of the studies comparing atomoxetine with immediate-release methylphenidate reported preliminary results only, from a study investigating relapse prevention, and was not powered for
comparisons between the two drugs;[25] despite this, statistical
comparisons were still reported and are included in this section. One
trial titrated atomoxetine recipients to a target dosage of atomoxetine 1.2 mg/kg/day (maximum permitted dosage was 1.4 mg/kg/
day); the extended-release mixed amfetamine salt dosage was increased in 10 mg increments at 1-week intervals to a final dosage of
30 mg/day.[26] One trial administered atomoxetine or osmotically
released methylphenidate with an individually tailored dosage, to
simulate the clinical setting.[51] The remaining trials titrated patients
according to therapeutic response, with permitted atomoxetine
dosages of 2,[25] 0.81.8,[23,24] 0.51.8[50] mg/kg/day, immediaterelease methylphenidate dosages of 560 mg/day[25] or 0.20.6 mg/
kg/day,[24] and osmotically released methylphenidate dosages of
1854 mg/day.[23] Where stated, the mean final dosages were
1.08,[51] 1.40 (among extensive metabolizers only),[25] 1.45,[23] 1.5,[50]
and 1.37[24] mg/kg/day for atomoxetine, and were 31.3 mg/day[25]
and 0.52 mg/kg/day[24] for immediate-release methylphenidate and
1.01[51] and 1.16[23] mg/kg/day for osmotically released methylphenidate. Certain limitations of these trials are discussed in section 8.
In the trial comparing atomoxetine with standard current
therapy, at baseline 75.3% of patients in the SCT arm received
only pharmacotherapy, 3.1% received simple behavioural
counselling, and 10.3% received both pharmacotherapy and
simple behavioural counselling; 11.3% received no treatment.[50] Pharmacotherapy included immediate-release methylphenidate (37.3%), extended-release methylphenidate
(47.0%), clonidine (3.6%), or combinations thereof (12%).
Eligible patients met DSM-IV criteria for ADHD (any subtype[23-25,50,51] or either combined or hyperactive/impulsive subtypes[26]), confirmed by K-SADS-PL[23,24,50] or an unspecified
K-SADS version,[25] and had to have an investigator-administered
ADHD-RS total score of 24,[51] 25 for boys and 22 for girls,[24]
1.5 SD above age and/or sex norms,[23,25,50] or >12 for a specific
subtype.[24] One trial required a CGI-S score of 4,[51] another
a CGI-ADHD-S score of 4.[24] Exclusion criteria included
other psychiatric disorders (except ODD;[51] e.g. depression,[26]
bipolar disorders,[23-26,50] anxiety disorders,[23,24,26] psychotic disorders[23-26,50]); a history of seizure,[23,26,50,51] tic disorder,[23-26,51]
mental retardation[51] or developmental disorder;[23,24,26,50,51]
Tourettes syndrome;[24-26,51] use of concomitant psychotropic
medication;[24,26,50,51] and serious medical illness.[25,50] Three
215
studies excluded patients who had not responded to previous

ADHD treatment.[23,25,51]
Primary endpoints were ADHD-RS investigator-administered total score (parent[25] or unspecified[51] version), CHIP-CE
total t-score,[50] SKAMP deportment score,[26] and response
(defined as a 40% reduction from baseline in ADHD-RS total
score) rate.[23,24] Additional endpoints included response rates
(see table III for definitions),[26,50,51] and ADHD-RS,[23,24,50,51]
CPRS,[23-25] CGI-ADHD-S,[23-25] CGI-S,[50] and SKAMP attention[26] scores. Two studies[23,26] also investigated HR-QOL,
using the PedsQL[26] or CHQ.[23]
The proportions of patients in treatment groups with ADHD of
the combined, inattentive and hyperactive/impulsive subtypes
ranged from 57% to 100%, from 0% to 39% and from 0% to 13%,
respectively.[23-26,50,51] The most common co-morbid disorders
(10% of patients) were ODD[23-25,50] and elimination disorders.[25]
Mean patient age ranged from 8.6 to 11.1 years,[23-26,50,51] and
69100% of patients were male.[23-26,50,51] A total of 2367% of
patients had received prior ADHD treatment.[23,24,51]
Where stated, assessments were based on the mITT population[23-26,50] using LOCF imputation.[23-25,50] Between-group
differences in baseline characteristics within each trial were either not significant[23,26] or accounted for in the analyses,[50,51]
except for one significant (p < 0.05) difference in sex proportions[25] and another (p < 0.05) in patient age.[24] Two trials were
noninferiority studies; noninferiority of atomoxetine to immediate-release methylphenidate[24] or osmotically released
methylphenidate[23] was established if the lower limit of the 95%
confidence interval (CI) for the difference between groups in
response rate was greater than -18%[24] or -15%.[23]
Atomoxetine did not differ significantly from[25] or was noninferior to[24] immediate-release methylphenidate, with regard to
the primary endpoints (change from baseline in ADHD-RS total
score[25] and response rate[24]) in children and adolescents with
ADHD (table III). In terms of response rate, the lower limit of the
95% CI for the difference between atomoxetine and immediaterelease methylphenidate was -11.7%.[24] Recipients of atomoxetine did not differ significantly from those receiving immediaterelease methylphenidate in the mean change from baseline on
ADHD inattention (-11.3 vs -12.0[24] and -9.9 vs -9.3[25]) or
hyperactivity/impulsivity (-9.7 vs -9.5[24] and -9.5 vs -8.5[25])
subscale scores, although both treatment groups showed scores
significantly lower than baseline (both p < 0.001).[24,25] Other
additional endpoints (CPRS and CGI-ADHD-S scores) did not
differ significantly between groups.[24,25]
Atomoxetine was significantly less effective than osmotically
released methylphenidate[51] and extended-release mixed amfetamine salts,[26] both controlled-release formulations of stimuPediatr Drugs 2009; 11 (3)
216
lants, in the change from baseline in ADHD-RS total score[51]

and SKAMP deportment score[26] (table III). In terms of response
rate, atomoxetine was not noninferior to osmotically released
methylphenidate (lower limit of the 95% CI for between-group
difference of -21%); the response rate was subsequently shown to
be significantly higher in osmotically released methylphenidate
recipients than in atomoxetine recipients (table III).[23] In addition, response rates were significantly higher with osmotically
released methylphenidate[51] or extended-release mixed amfetamine salts[26] than with atomoxetine in two other trials (table III).
Mean SKAMP attention score improvement was also significantly lower among atomoxetine than extended-release mixed
amfetamine salt recipients (-0.08 vs -0.49; p < 0.001),[26] and atomoxetine recipients demonstrated a significantly (p < 0.01) lower
improvement on the CPRS and CGI-ADHD-S scales compared
with recipients of osmotically released methylphenidate.[23]
In a subanalysis, the response rates among stimulant-exposed patients (n = 301) receiving atomoxetine versus osmotically released methylphenidate were significantly different
(37% vs 51%; p = 0.03) and only osmotically released methylphenidate differed significantly from placebo (23%; p = 0.002);
however, among stimulant-naive patients (n = 191), the two
active treatment groups did not differ significantly from each
other (57% vs 64%) and both differed significantly from placebo (25%; p = 0.004 and p 0.001, respectively).[23]
When compared with standard current therapy, atomoxetine
had a significantly greater positive impact on HR-QOL, as
assessed by the mean CHIP-CE total t-score at endpoint[50]
(table III). Atomoxetine was also significantly more effective than
standard current therapy in terms of ADHD-RS total score and
response rate at endpoint (table III), as well as on the ADHD-RS
subscale scores (inattention 12.1 vs 17.3; p < 0.001; hyperactivity/
impulsivity 11.3 vs 16.3; p < 0.001).[50] Atomoxetine was associated with a significant improvement versus standard current
therapy with regard to CGI-S score (p < 0.001).[50]
4.3 In Patients with Co-Morbid Conditions
While most of the major efficacy trials investigating atomoxetine have allowed the inclusion of patients with co-morbid
ODD, other disorders are also common in patients with ADHD,
and were either not permitted in these trials or patient numbers
with these co-morbid disorders were low. Therefore, randomized,
double-blind, placebo-controlled trials,[52-57] mainly of multicenter design,[52-55,57] have been conducted in patients with comorbid anxiety disorders,[52,53] depressive disorders,[53,55] tic disorders (including Tourettes syndrome),[57] and autism spectrum
disorders (including Aspergers syndrome).[56] An additional trial
in patients with ADHD and co-morbid ODD has also been

conducted.[54]
Eligible patients were children or adolescents (aged 518 years;
mean 9.314.6 years)[52-57] with a DSM-IV diagnosis of ADHD[52-57]
and a total or subscale ADHD-RS score of 1.5 SD above age
and sex norms,[52,55,57] and/or a Childrens Depression Rating
Scale-revised total score >36[53] or 40.[55] Patients were also required to have a DSM-IV diagnosis of an anxiety disorder,[52,53]
depressive disorder,[53] major depression,[55] Tourettes syndrome,[57] tic disorders,[57] autism spectrum disorder,[56]
or ODD.[54] Diagnoses were confirmed using the K-SADSPL.[52-55,57] One study[52] focused on patients who did not
respond during the placebo lead-in period, based on a 25%
reduction in Pediatric Anxiety Rating Scale (PARS) score.
Patient numbers ranged from 16[56] to 226,[54] with most studies
involving between 100 and 200 patients.[52,53,55,57]
Not all primary endpoints related to efficacy with regard to
ADHD (most focused on both ADHD and the co-morbid
condition,[52,54-57] one focused on tolerability[53]); the main
ADHD endpoints of each trial (ADHD-RS total,[52,53,55,57]
DSM-IV ADHD symptoms,[56] and SNAP-IV ADHD subscale[54] scores) are focused on in this section.
Patients did not receive concomitant psychotropic treatment
for their co-morbid conditions in most studies;[52,54-57] the one
exception[53] involved all patients receiving atomoxetine and
being randomized to fluoxetine or placebo.
The efficacy of atomoxetine does not appear to be affected by
the presence of co-morbid disorders, and symptoms of the
co-morbid disorders were either not adversely affected or improved in these studies.[52-57] Atomoxetine was more effective
than placebo in the treatment of ADHD in patients with comorbid anxiety disorders (mean change in ADHD-RS total score
of -10.5 vs -1.4; p < 0.001),[52] major depression (mean change in
ADHD-RS total score of -13.3 vs -5.1; p < 0.001),[55] tic disorders
(including Tourettes syndrome) [mean change in ADHD-RS
total score of -10.9 vs -4.9; p < 0.01],[57] autism spectrum disorders (mean DSM-IV ADHD hyperactive/impulsive symptom
score at endpoint of 10.4 vs 14.5; p < 0.01; no significant betweengroup difference in inattentive symptom score),[56] and ODD
(mean change in SNAP-IV ADHD hyperactive/impulsive subscale score of -4.6 vs -2.2; p < 0.01; change in inattentive subscale
score of -5.0 vs -2.2; p < 0.001).[54]
In general, symptoms of co-morbid conditions were not worsened by the use of atomoxetine;[54,55,57] for example, in children
with co-morbid tic disorder Yale Global Tic Severity Scale total
scores in atomoxetine recipients did not differ significantly from
those in placebo recipients (-5.5 vs -3.0) and Tic Symptom SelfReport total scores were -4.7 and -2.9, while Clinical Global
217
Impressions tic/neurologic severity scale scores were significantly

improved with atomoxetine (-0.7 vs -0.1; p = 0.002).[57]
In addition, in some trials[52,56] the co-morbid conditions
were improved by treatment with atomoxetine; for example, in
patients with anxiety disorders Pediatric Anxiety Rating Scale
scores in atomoxetine recipients were significantly improved
with respect to placebo (-5.5 vs -3.2; p < 0.012).[52]
When administered alone, atomoxetine did not significantly
differ from atomoxetine plus fluoxetine with regard to ADHD
(mean change in ADHD-RS total score of -20.5 vs -24.0) or
anxiety symptoms (mean change in Multidimensional Anxiety
Scale for Children score of -11.3 vs -13.4).[53] Depression
measures were inconclusive in this study: there was a significant
difference between groups in favor of combination treatment in
the change in mean Childrens Depression Inventory score
(-5.4 vs -8.8; p = 0.43), but no significant difference was found
in the change in mean Childrens Depression Rating ScaleRevised score (-17.6 vs -20.4).
5. Tolerability
This section focuses primarily on data from the US prescribing information,[10] supplemented by data from two metaanalyses[65,66] and the trials reported in section 4.[23-26,37-43,46,47,50-57]
Oral atomoxetine was generally well tolerated in children and
adolescents with ADHD. Common (5% of atomoxetine recipients and reported by numerically more atomoxetine than placebo
recipients) adverse events from placebo-controlled trials of 18
weeks duration are shown in figure 1, and included headache,
abdominal pain, decreased appetite, vomiting, somnolence, and
nausea.[10]
ATO
PL
Dizziness
Irritability
Fatigue
Nausea
Somnolence
Vomiting
Decreased appetite
Abdominal pain
Headache
0
10
15
Incidence (% patients)
20
Fig. 1. Tolerability of oral atomoxetine (ATO) in pediatric patients with

attention-deficit hyperactivity disorder. Incidence of common (5% of ATO
recipients [n = 1597] and reported by numerically more ATO recipients than
placebo [PL] recipients [n = 934]) treatment-emergent adverse events associated with ATO and PL. Data from trials of 18 weeks duration.[10]
In individual placebo-controlled trials, significantly (p < 0.05)

more atomoxetine than placebo recipients reported decreased
appetite (1836% vs 417%),[38-40,42,43] somnolence (1517% vs
24%),[42,43] vomiting (15% vs 1%),[38] nausea (1217% vs
02%),[38,40] asthenia (11% vs 1%),[38] fatigue (10% vs 2%),[43] and
dyspepsia (9% vs 0%).[38]
Where reported, the severity of adverse events among atomoxetine recipients was generally classified as mild[51] or mild
to moderate.[24,26,50,55] Most studies either did not report the incidence of serious adverse events[23,25,37,38,40,41,43,46,47,52-54] or stated
that there were none among atomoxetine recipients.[26,39,42,50,55,57]
Where reported, serious adverse events included aggressive behavior,[56] partial seizure,[24] and prolonged crying (fear of death),[51]
and had a low incidence.
A total of 3% of atomoxetine recipients (48 of 1613) versus
1% of placebo recipients (13 of 945) discontinued treatment
because of adverse events in short-term studies, with adverse
events leading to discontinuation including irritability, somnolence, aggression, nausea, vomiting, abdominal pain, constipation, fatigue, feeling abnormal, and headache.[10]
Atomoxetine appears better tolerated among extensive metabolizers than poor metabolizers. The US prescribing information reported that adverse events occurring in 5% of
poor metabolizers and either twice as frequently or significantly
(p-value not stated) more frequently among poor metabolizers
than extensive metabolizers included tremor (5% vs 1%), depression (7% vs 4%), constipation (7% vs 4%), decreased weight
(7% vs 4%), and insomnia (15% vs 10%).[10] A pooled analysis
of 14 studies reported significant differences between poor
(n = 237) and extensive (n = 3017) metabolizers receiving atomoxetine in the incidence of decreased appetite (24% vs 17%;
p = 0.008), insomnia (11% vs 7%; p = 0.035), abrasion (5% vs
2%; p = 0.012), and tremor (5% vs 1%; p < 0.001).[61]
Atomoxetine appears generally well tolerated in the longterm treatment of children and adolescents with ADHD. Discontinuations due to adverse events in long-term placebocontrolled trials among atomoxetine versus placebo recipients
occurred in 3%[47] and 1%[46] versus 1%[47] and 1%.[46] A total of
66% atomoxetine versus 54% placebo recipients reported at
least one new or worsened adverse event.[47] Common adverse
events included headache (10% atomoxetine vs 9% placebo
recipients) and nasopharyngitis (8% vs 9%).[46]
Atomoxetine appears associated with weight loss to varying
degrees in comparison with other ADHD medication. Overall, in
placebo-controlled trials the incidence of weight loss was 3% of
atomoxetine vs 0% of placebo recipients.[10] Long-term placebocontrolled trials demonstrated that a switch to placebo was associated with a greater increase in weight than atomoxetine
218
continuation (weight +3.3 vs +1.2 kg; p < 0.001;[47] weight percentile +9.9 vs +0.72; p < 0.001[46]). Of the active comparator
studies, one[24] found significantly (p < 0.001) greater weight loss
among atomoxetine versus immediate-release methylphenidate
recipients (-1.2 vs -0.4 kg), and one[23] found significantly lower
weight loss among atomoxetine versus osmotically released methylphenidate recipients (-0.6 vs -0.9 kg; p < 0.05). Where reported in the other active comparator trials, weight loss did not
differ significantly between treatment groups.[25,50] Longer term
weight data (5 years) are presented in section 2.2, and imply that
this weight loss is not permanent.
Where reported, no clinically significant changes in laboratory test values occurred in any of the short-[23-25,40,42,43] or
long-[46,47] term trials.
Atomoxetine was associated with a significantly (p < 0.05)
greater incidence of somnolence (1126% vs 04%),[24,25] nausea
(20% vs 10%),[24] vomiting (12% vs 04%),[24,25] anorexia (37% vs
25%),[24] and dizziness (15% vs 7%)[24] compared with immediaterelease methylphenidate. Immediate-release methylphenidate
was associated with a significantly (p < 0.05) greater incidence of
abnormal thinking than atomoxetine (5% vs 0%).[25] One study
found that the incidence of discontinuation due to adverse events
did not differ significantly between groups;[25] another showed
significantly (p < 0.05) more atomoxetine than immediate-release
methylphenidate recipients discontinued because of treatmentemergent adverse events (11% vs 4%), and had an overall significantly (p < 0.001) greater incidence of treatment-emergent
adverse events (87% vs 68%).[24]
In one study comparing atomoxetine with osmotically released
methylphenidate and placebo,[23] recipients of atomoxetine had a
significantly (p < 0.05) greater incidence of somnolence compared
with osmotically released methylphenidate but not placebo (6% vs
2% and 4%), whereas osmotically released methylphenidate was
associated with a significantly (p < 0.05) greater incidence of insomnia compared with atomoxetine and placebo (13% vs 7%
and 1%).[23] Both atomoxetine and osmotically released methylphenidate were associated with a significantly higher incidence of
decreased appetite compared with placebo (14% and 17% vs 3%),
but did not differ significantly from each other. Atomoxetine was
associated with a significantly higher rate of any treatment-emergent adverse events than placebo (67% vs 54%); osmotically released methylphenidate did not differ from either other treatment
group in this measure (67%).[23] In the other study comparing atomoxetine to osmotically released methylphenidate, adverse events
included somnolence (4% of atomoxetine vs 1% of osmotically
released methylphenidate recipients), nausea (5% vs 1%), fatigue
(3% vs 0%), insomnia (2% vs 6%), and decreased appetite (3% vs
6%).[51] Atomoxetine and osmotically released methylphenidate
recipients did not differ significantly in overall incidence of adverse events, the incidence of treatment-related adverse events, or
the incidence of discontinuations due to adverse events.
In the trial comparing atomoxetine with extended-release
mixed amfetamine salts, the most commonly occurring treatment-related adverse events among atomoxetine recipients were
somnolence (19% of patients), decreased appetite (18%), upper
abdominal pain (15%), and headache, and among extendedrelease mixed amfetamine recipients were insomnia (28% of patients), decreased appetite (28%), upper abdominal pain (19%),
and anorexia (17%).[26] In this study, a total of 73% of atomoxetine versus 85% of extended-release mixed amfetamine salt recipients reported treatment-emergent adverse events, 65% versus
74% reported a study medication-related adverse event, and 4%
and 7% discontinued treatment because of adverse events.[26]
A pooled analysis using data from two open-label atomoxetine studies demonstrated that the initiation of therapy using a
twice-daily divided dose regimen compared with a once-daily
regimen could potentially decrease the risk of adverse events
within the first few weeks of treatment.[67] The incidence of
decreased appetite in the first 2 weeks was significantly higher
among once-daily than among twice-daily atomoxetine recipients (14% vs 8%; p = 0.036), as was somnolence (14% vs 4%;
p < 0.001). The incidence of headache was, however, lower
among once-daily recipients (7% vs 17%; p = 0.003).
Discontinuation of atomoxetine appears to be well tolerated.
A prospective pooled analysis of two 9- to 10-week trials in
children aged 712 years with ADHD demonstrated that after a
1-week discontinuation phase, during which all patients received
placebo in a single-blind manner, there was a low incidence of
discontinuation-emergent adverse events, and no significant differences were observed between patients previously receiving
atomoxetine and those receiving placebo throughout.[45]
5.1 Specific Adverse Events
The US prescribing information carries a black-box warning

regarding suicidal ideation in children and adolescents; it appears
to be more common among atomoxetine than placebo recipients.[10] A meta-analysis including 14 pediatric clinical trials
(12 placebo-controlled and 5 including a methylphenidate treatment arm) was conducted investigating the suicidality of patients
aged 618 years receiving atomoxetine.[66] No suicides occurred in
the trials included in the meta-analysis. The frequency of suicidal
ideation was greater among atomoxetine (n = 1357) than placebo
(n = 851) recipients (0.37% vs 0%; incidence difference 0.46; 95%
CI 0.09, 0.83; p = 0.016), but did not differ significantly between
atomoxetine (n = 558) and methylphenidate (n = 464) recipients
(0.18% vs 0.22%; incidence difference -0.12; 95% CI -0.62, +0.38).

All patients with suicidal ideation in placebo-controlled trials
were male and aged between 7 and 12 years. With atomoxetine,
the number needed to harm for an additional suicide-related
event was 227; the number needed to treat for achievement of
remission of ADHD symptoms was 5.[66] Patients starting atomoxetine therapy should be closely monitored for suicidal thinking
and behavior, clinical worsening, or unusual changes in behavior.[10]
Rarely, atomoxetine may be associated with severe liver injury.[10] A retrospective study investigated the incidence of liverrelated adverse events in pediatric and adult patients treated with
atomoxetine in clinical trials, as well as among spontaneous postmarketing reports of adverse events.[65] Among recipients of
atomoxetine in clinical trials, 41 of 7961 (0.5%) had hepatobiliary
events that were considered possibly related to atomoxetine; most
of these were mild increases in ALT or AST levels.[65] Four years
after the market launch of atomoxetine, a total of 351 liverrelated adverse events had been reported (among a total of
4 328 000 recipients of atomoxetine; <0.01%). Of these, 69 were
explainable by factors unrelated to atomoxetine, 146 had too little
information to assess fully, 133 had possible confounding factors
and were deemed possibly atomoxetine-related, and 3 found
atomoxetine to be probably related. These three patients all recovered after atomoxetine discontinuation.[65] Patients who have
jaundice or laboratory evidence of liver injury should discontinue
atomoxetine treatment; treatment should not be re-initiated.[10]
There is the potential for cardiovascular effects with atomoxetine administration. Both the US[10] and the UK[11] prescribing information include precautions regarding cardiovascular
effects. Caution should be used when prescribing atomoxetine to
children and adolescents with serious structural cardiac abnormalities[10,11] (a cardiac specialist should be consulted in these
patients)[11] or other serious heart problems,[10] as sudden death
has been reported in these patients;[10,11] caution should also be
used in patients with congenital long QT interval, acquired long
QT interval, or a family history of QT prolongation.[11] There
have been post-marketing spontaneous reports of prolonged QT
intervals during atomoxetine administration.[10,11]
In a pooled analysis of placebo-controlled trials, 2.5% (36 of
1434 patients) of atomoxetine and 0.2% (2 of 850) of placebo
recipients demonstrated a heart rate of at least 110 bpm plus an
increase in heart rate of 25 bpm at endpoint.[10] A total of 4.8%
(59 of 1226) of atomoxetine and 3.5% (26 of 748) of placebo had
high SBP at endpoint; corresponding proportions of patients
with high DBP at endpoint were 4.0% (50 of 1262) and 1.1%
(8 of 759).[10] Caution should be used when administering
atomoxetine in patients with hypertension,[11] tachycardia,[11]
other conditions associated with abrupt heart rate or BP
219
changes,[10] cardiovascular disease,[11] or cerebrovascular disease,[11] as well as in patients with hypotension.[10,11]

A study conducted by FDA officials indicates that atomoxetine use (as well as other ADHD medication use) is potentially
associated with hallucinations and other psychotic symptoms.[68]
In a pooled analysis from 49 randomized, placebo-controlled
clinical trials of extended-release mixed amfetamine salts (four
trials), dexmethylphenidate (seven trials), extended-release
methylphenidate (tablets [four trials] and capsules [four trials]),
long-acting extended-release methylphenidate (three trials), methylphenidate transdermal system (eight trials), modafinil (five
trials), and atomoxetine (14 trials), the rate of psychosis/mania
events per 100 person-years was 1.48 in the drug group compared
with 0 in the placebo group. Of the eleven psychosis/mania events
occurring in the pooled drug group, four occurred among atomoxetine recipients.[68]
There have been post-marketing spontaneous reports of
seizures.[10,11] No fatal overdoses occurred in clinical trials, and
there have been no post-marketing reports of death by overdose
with atomoxetine alone.[10]
6. Pharmacoeconomic Considerations
This section provides a brief overview of recent pharmacoeconomic analyses of atomoxetine in the treatment of children[69-72] and adolescents[70] with ADHD. The cost effectiveness
of atomoxetine compared with other treatments (immediate- or
extended-release methylphenidate,[69-72] dexamfetamine,[69,71] tricyclic antidepressants,[71] or no medication[69,70,72]), as a costutility analysis, has been investigated in one fully published
paper[69] and three abstracts with attached posters[70-72] (table IV).
All four analyses used a Markov model, incorporating 10,[72]
14,[70] 18,[69] or 22[71] health states, to estimate the costs and benefits of the treatment strategies, and estimated the incremental
cost per quality-adjusted life-year (QALY) gained with atomoxetine versus the comparator strategies.[69-72] A survey of 83 parents
of children with ADHD provided utility values for all four studies, and efficacy and safety of the involved treatments were based
on a review of controlled clinical trials and other clinical literature.[69-72] Costs and outcomes were estimated using a Monte
Carlo simulation, with a time horizon of 1 year;[69-72] costs were
estimated from the perspective of the National Health Service in
England and Wales,[69] Dutch society,[71] the German health service,[72] and the Norwegian healthcare system.[70] All four studies
included direct costs[69-72] (two studies only included study drug
costs[69,72] ), with one study also including indirect costs.[71]
All four studies divided patients into three groups: stimulantnaive, stimulant-failure, and stimulant-contraindicated.[69-72] The
220
Table IV. Pharmacoeconomic evaluation of atomoxetine vs other or no medication in children[69-72] and adolescents[70] with attention-deficit hyperactivity
disorder (ADHD). Incremental cost per quality-adjusted life-year (QALY) gained, estimated using a Markov model with a time horizon of 1 year
Study
Cottrell et al.
Perspective
[69]
Year of
Incremental cost per QALY gained
costing
stimulant-naive pts
stimulant-failed pts
stimulant-contraindicated pts
IM MPH
ER MPH
DA IR
TCA
d14 945
NHS in England and Wales
2004
d15 224
d13 241
Diamantopoulos et al.[72]b
German health service
NR
h18 227
h7778
Laing et al.[71]b
Dutch societal
NR
h18 831
h22 804
Tilden et al.[70]b
Norwegian healthcare system
2005
h25 463c
h19 162c
no med
no med
d11 523/12 370a
h14 385
h13 120
h14 916
Dominant
h21 497c
h22 385c
a Stimulant-naive/-exposed patients.
b Available as abstract plus poster.
c Converted from Norwegian kroner (NOK) using the exchange rate as at 13/10/2005 of NOK1 = h0.12784.
DA IR = dexamfetamine immediate release; ER MPH = extended-release methylphenidate; IM MPH = immediate-release methylphenidate; NHS = National
Health Service; no med = no medication; NR = not reported; pts = patients; TCA = tricyclic antidepressants.
fully published study also included stimulant-averse patients

(results for this group are not reported here), and further split the
stimulant-contraindicated patients into stimulant-naive and -exposed.[69] Treatment algorithms differed slightly between studies,
but involved an atomoxetine-based algorithm versus a comparator algorithm, with numbers of treatments in each algorithm
ranging from two to five for stimulant-naive patients, one to four
for stimulant-failed patients, and one to three for stimulantcontraindicated patients.
Initial atomoxetine treatment algorithms appear cost effective
versus algorithms involving initial methylphenidate (immediateor extended-release), dexamfetamine, tricyclic antidepressants, or
no treatment in stimulant-naive, -failed, and -contraindicated
children and adolescents with ADHD (table IV).[69-72] The incremental cost per QALY gained was below commonly accepted
cost-effectiveness thresholds.[69-72] Sensitivity analyses demonstrated that the models were robust to changes in most variables;
however, utility values were shown to be important indicators of
cost effectiveness.[69-72]
An additional study (available as a poster) investigating the
cost effectiveness of atomoxetine versus placebo with regard to
societal costs in Sweden found that placebo was dominated by
atomoxetine.[73] Costs were taken from 2005 databases, with an
exchange rate of h1 = 9.2 Swedish kronor, and included both indirect and direct costs. Stimulant-naive patients with ADHD
(aged 715 years) were randomized to 10 weeks of treatment with
atomoxetine or placebo; both groups received additional parental
training. Atomoxetine was associated with a significantly greater
least squares mean change from baseline in ADHD-RS score
(-19.0 vs -6.3; p < 0.001), and total cost (excluding costs due to
loss of leisure time) decreased among atomoxetine recipients and
increased among placebo recipients (-h349 vs +h246; p = 0.002).
Pharmacoeconomic analyses of atomoxetine, in common with

all pharmacoeconomic analyses, are subject to a number of limitations. Pharmacoeconomic analyses based on clinical trials extrapolate the results of such trials to the general population;
however, patient populations, rates of compliance, and major
outcomes in clinical trials may differ from those observed in reallife practice. Modeled analyses, such as those presented in this
section, rely on a number of assumptions and use data from a
variety of sources. Results of pharmacoeconomic analyses may
not be applicable to other geographical regions because of differences in healthcare systems, medical practice, and unit costs.
7. Dosage and Administration

Atomoxetine is indicated in various countries including the
US[10] and the UK[11] for the treatment of children and adolescents with ADHD;[10,11] atomoxetine is approved for use in
children aged 6 years in the UK.[11]
Table V. Summary of recommended atomoxetine dosage and administration in pediatric patients according to bodyweight.a Local prescribing information should be consulted for further details
Atomoxetine
dosage
70 kg
(mg/kg/day)
>70 kg
(mg/day)
Initial dosage
0.5
40
Target dosageb
1.2
80
Maximum dosage
1.4 (US)
100
a According to both US[10] and UK[11] labeling unless otherwise specified.

b The minimum period before the first dose increment is 3 days in the US[10]
or 7 days in the UK.[11]
Recommended atomoxetine dosages and the administration

schedule are presented in table V. No additional benefit has been
shown for atomoxetine dosages exceeding 1.2 mg/kg/day.[10,11]
Atomoxetine can be taken with or without food, and can be
discontinued without tapering.[10,11] Capsules should be taken
whole.[10] Atomoxetine can be administered either as a single
daily dose in the morning, or as evenly divided doses in the
morning and late afternoon or early evening.[10]
The US prescribing information contains a black-box
warning regarding suicidal ideation (section 5).[10]
Initial and target atomoxetine dosages should be halved in
patients with moderate hepatic impairment (Child-Pugh class B)
and reduced by three-quarters in patients with severe hepatic impairment (Child-Pugh class C).[10,11] No dosage adjustment is required for patients with end-stage renal disease or lesser degrees
of renal insufficiency.[10,11] In the UK, in patients who are known
to be poor metabolizers or who are receiving concomitant CYP2D6
inhibitors, such as paroxetine, a lower starting dose and slower
dosage up-titration than extensive metabolizers should be considered.[11] In the US, patients who are either poor metabolizers
or who are receiving concomitant strong CYP2D6 inhibitors are
recommended to initiate treatment at the normal dosage, but
only increase to the normal target dosage if no response has occurred after 4 weeks and if the initial dosage is well tolerated.[10]
Local prescribing information should be consulted for contraindications, precautions and warnings, drug interactions,
dosage modifications, and patient monitoring requirements.
8. Place of Atomoxetine in the Management of
Attention-Deficit Hyperactivity Disorder
The main aim of therapy for ADHD patients is to improve
psychologic functioning (including academic, family, and social
functioning),[74] i.e. the core symptoms of ADHD. Both behavioral
and pharmacologic therapies, as well as psychoeducation, are recommended.[74] Current treatment guidelines recommend the
first-line use of psychostimulants (e.g. methylphenidate) and/or
psychosocial intervention for the treatment of children (aged over
6 years) and adolescents with ADHD, particularly if no co-morbid
condition is present.[64,74,75] Second-line therapies include a different stimulant or atomoxetine.[64,75] In the case of patients with
ADHD and co-morbid anxiety, first-line treatment is either atomoxetine (to treat both disorders) or a stimulant (to treat the
ADHD) plus a serotonin reuptake inhibitor (to treat the anxiety).[64,74] Atomoxetine may also be a first-line therapy for patients
with co-morbid tics.[74] Patients unable to take stimulants because
of an active substance abuse disorder or previous adverse effects
are advised to take atomoxetine as a first-line therapy.[74,76] Other
221
potential (but not US FDA-approved) therapies include bupropion, tricyclic antidepressants, and a-adrenergic agonists.[74]
While the immediate-release formulations of methylphenidate and amfetamines have been shown to be effective in
ADHD, they require multiple daily doses to achieve the optimal
effect, and can potentially be associated with abuse or misuse.[77] Longer acting, once daily, extended-release formulations of stimulants are just as effective as immediate release, and
are easier to administer; however, they may be associated with
pharmacokinetic variability, as they rely on pH and gastrointestinal transit time for delivery of the active ingredient.[77]
Atomoxetine is the first drug not classified as a stimulant to be
approved for ADHD, and, unlike stimulants, is not a controlled
substance.[78] It also has low to no abuse or misuse potential.[79]
The issue of stimulant abuse is, however, controversial. It has
been stated that patients who are being administered therapeutic
dosages of stimulants for the treatment of ADHD do not normally have a problem with abuse; in fact, there is the possibility
that stimulant treatment may reduce the chance of substance
abuse in ADHD patients.[79] More emphasis is placed on the risk
of diversion of immediate-release stimulants for recreation or
performance enhancement (extended-release formulations can be
used, but it is more difficult to extract the drug).[79]
In well designed clinical trials of 69 weeks duration, atomoxetine was effective in pediatric patients (including stimulantnaive patients) with ADHD, demonstrating greater improvements
from baseline in efficacy measures than placebo (sections 4.1.1 and
4.1.3). Atomoxetine was also effective in preventing relapse in
longer term trials; its efficacy was maintained for at least 2 years
(section 4.1.2). Atomoxetine, despite a half-life of just over 3 hours,
shows efficacy into the evening if given as a single morning dose
(section 4.1.1), and can be administered either as a single dose or
two evenly divided doses (section 7).[10] However, a recent study
has shown that the risk of some adverse events may be lower if
atomoxetine is initiated as a twice-daily regimen (section 5).[67]
Prospective trials are required to confirm this possibility.
Co-morbid disorders (such as anxiety disorders, depressive
disorders, tic disorders, and autism spectrum disorders), common
in ADHD patients, were either not affected or improved on administration of atomoxetine, and efficacy with regard to ADHD
was not affected by the presence of co-morbidities (section 4.3).
However, four[53,54,56,57] of the six[52-57] trials in patients with comorbid disorders did not have ADHD symptom measures as their
primary endpoints, and thus definitive conclusions with regard to
the efficacy of atomoxetine cannot be drawn from these studies.
Comparisons with other ADHD medications revealed
mixed results with regard to primary efficacy measures.
Atomoxetine appeared more effective than standard current
222
therapy (any combination of medicines [immediate- or extendedrelease methylphenidate or clonidine] and/or behavioral counseling, or no treatment) and as effective as, or noninferior to,
immediate-release methylphenidate, but less effective than osmotically released methylphenidate or extended-release mixed
amfetamine salts (section 4.2). However, the extended-release
mixed amfetamine salts study[26] and one of the osmotically
released methylphenidate studies[51] were of only3 weeks duration; full benefits of atomoxetine often take several weeks
(potentially up to 8 weeks)[8] to occur.[2,8,63,64] Studies involving
a longer treatment period are required before conclusions can
be drawn in these comparisons. Also, one of the immediaterelease methylphenidate studies[25] was not powered for a direct
comparison, and should only be used as supporting data for the
other immediate-release methylphenidate study.[24]
The studies had other potential limitations. Three of the
active comparator trials were open-label,[25,50,51] and only one
was placebo controlled.[23] The comparison of atomoxetine
with extended-release mixed amfetamine salts[26] was conducted in a laboratory classroom, and thus different from a
normal classroom atmosphere; all children had ADHD (rather than a small proportion), and the number of observers and
staff was higher than in an average non-laboratory classroom.
This study also excluded patients with the inattentive subtype
of ADHD, thus not allowing comparison in these patients.[26]
The two studies investigating atomoxetine versus osmotically
released methylphenidate both excluded, for ethical reasons,
patients with no response to previous methylphenidate treatment, thus introducing a possible methylphenidate-slanted
bias.[23,51] Patients with tic[23,51] or anxiety disorders[23] were
also excluded, again for ethical reasons, which would also potentially bias results in favor of methylphenidate (which is
contraindicated in these disorders), as atomoxetine may potentially be more beneficial in these populations.
Interestingly, the significant difference in efficacy observed
between atomoxetine and osmotically released methylphenidate
was not present when only the stimulant-naive patients in the
population of one study were investigated;[23] stimulant-exposed
patients still demonstrated a significant treatment difference
(section 4.2). This may reflect study design, as the trial excluded
patients with no response to previous methylphenidate treatment.
Overall, the impact of atomoxetine treatment on HR-QOL
appears positive. In shorter term, placebo-controlled trials,
HR-QOL either stayed constant or was improved, and longer
term, placebo-controlled trials also demonstrated positive effects (sections 4.1.1, 4.1.2, and 4.1.3). HR-QOL was also improved to a greater extent with atomoxetine than with standard
current therapy (section 4.2).
Pharmacoeconomic analyses suggest that initial atomoxetine treatment appears cost effective compared with initial
methylphenidate (both immediate- and extended-release),
dexamfetamine, tricyclic antidepressants or no treatment (section 6), demonstrating a cost per QALY that was below commonly accepted cost-effectiveness thresholds.
Several of the most commonly occurring adverse events with
atomoxetine administration were generally consistent with increased noradrenergic tone (e.g. somnolence, vomiting) [section 5];
other common adverse events included headache and decreased
appetite. Adverse events were generally classified as mild or
moderate, and serious adverse events were rare. An increase in
suicidal ideation among atomoxetine versus placebo recipients led
to a black-box warning for children and adolescents (section 5.1).
Rarely, severe liver injury may also occur in atomoxetine recipients, with three reports of liver-related adverse events deemed
probably related to atomoxetine treatment in the 4 years following
its market launch. There have also been reports of sudden death in
patients with serious structural cardiac abnormalities and other
serious heart problems receiving atomoxetine. Discontinuation of
atomoxetine is well tolerated, with a low incidence of discontinuation-emergent adverse events and no evidence of symptom rebound (sections 4.1.1 and 5). In contrast, there has been
some anecdotal evidence of symptom rebound and discontinuation-emergent adverse events following withdrawal of stimulants,
with dexamfetamine potentially causing more rebound than
methylphenidate.[80]
Slight differences were noted in the adverse events profiles of
atomoxetine and extended-release stimulants, probably reflecting
differences in their mechanisms of action (e.g. atomoxetine appeared more commonly associated with somnolence, osmotically
released methylphenidate with insomnia). The adverse event
profile of atomoxetine also differed somewhat to that of immediate-release methylphenidate; for example, atomoxetine was
associated with a significantly higher incidence of somnolence,
nausea, vomiting, anorexia, and dizziness (section 5).
In contrast, stimulants are commonly associated with appetite
suppression, stomach pain, insomnia, and weight loss.[4] There is
also a possible potential for tic disorders and growth effects, as
well as potential cardiovascular problems; the US prescribing
information for mixed amfetamine salts includes a black-box
warning regarding cardiovascular disorders, and other stimulants
carry contraindications and warnings for patients with cardiovascular conditions.[4] However, with stimulants only two nonfatal adverse cardiovascular events occur per million
prescriptions, and less than one death occurs per million.[80] Stimulant treatment effects on growth is controversial.[80] There
is evidence that growth is affected by many factors, and thus it is
possible that differences in height and weight are the result of

other causes; however, the possibility cannot be ruled out that
stimulants are associated with significantly stunted growth, as
several meta-analyses and trials appear to demonstrate.[80]
Statistically, but not clinically, significant increases in heart
rate and BP occur with atomoxetine administration (section 2.2),
with few patients experiencing increases in heart rate or BP to
abnormal levels (section 5.1); however, additional longer term
data would be of use in expanding our knowledge of the cardiac
effects of atomoxetine. There is also an initial loss in expected
weight and height among atomoxetine recipients, although both
measures return to expected measurements after a period of time
(section 2.2). However, it has been suggested that a weakness of
this study was that growth was only monitored sporadically.[80]
As atomoxetine is mainly metabolized via the CYP2D6 enzymatic pathway, it remains in the system of poor metabolizers
of CYP2D6 substrates for longer than extensive metabolizers,
and at higher concentrations (section 3); thus, these patients are
more prone than extensive metabolizers to the adverse events
associated with atomoxetine (section 5). However, this can be
managed satisfactorily by decreasing the dosage administered
to these patients (section 7). A recent study has, interestingly,
shown that genotyping is not necessary to safely administer
atomoxetine: investigators in the trial were able to administer
atomoxetine to similar efficacy and safety levels regardless of
metabolizer status, without prior knowledge of whether the
patients were extensive or poor metabolizers.[81]
A common co-morbid problem among pediatric patients
with ADHD is disordered sleep, specifically reduced sleep time
and more total interrupted sleep time, as well as more daytime
sleepiness and difficulty getting up, compared with healthy
controls.[82] Atomoxetine appears less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with
ADHD (section 2.2).
Higher dosages of atomoxetine are not associated with a
greater improvement in efficacy, and thus there appears to be no
advantage to increasing atomoxetine dosages beyond the current
guidelines. Two randomized, double-blind studies involving
atomoxetine nonresponders aged 616 years demonstrated no
significant difference in ADHD-RS total scores between recipients of atomoxetine 1.2 or 1.8 mg/kg/day (usual dosage) and
those receiving the increased dosage of 3.0 or 2.4 mg/kg/day.[83]
The potential for lower (off-label) target dosages in the
longer term treatment of ADHD has been investigated. In two
studies, responders to short-term atomoxetine treatment were
randomized to lower (0.5[84] or 0.8[85] mg/kg/day) versus higher
(1.21.8[84] or 1.4[85] mg/kg/day) dosages of atomoxetine. Both
showed that the mean change in ADHD-RS total score from
223
baseline did not significantly differ between groups after 8[84]

and 10[85] months therapy.[84,85] However, a significant
(p = 0.017) loss of benefit (in terms of ADHD-RS total scores)
versus baseline was shown in patients receiving a lower dosage;
patients receiving a higher atomoxetine dosage did not differ
significantly from baseline in this measure.[84]
Very young children (aged under 6 years) with ADHD have
not been extensively studied.[3] The majority of methylphenidate
studies have included school-age children; very few have involved
preschoolers, and, despite an FDA warning against administration to children under the age of 6 years, methylphenidate is often
prescribed off-label for these patients.[3] Atomoxetine appears
potentially effective in this patient group. One noncomparative
pilot study involving 22 children with ADHD, aged 56 years,
demonstrated that atomoxetine to a maximum dosage of
1.8 mg/kg/day was generally effective with regard to core ADHD
symptoms.[86] A large, randomized, placebo-controlled study of
atomoxetine is ongoing in children with ADHD aged 56 years.[3]
Although atomoxetine has been extensively researched, additional data are needed. Of interest would be a well designed, longterm safety study, prospectively investigating, for example, the
weight and height differences of atomoxetine recipients compared with placebo and active comparators. A greater number of
trials to augment the discoveries in patients with co-morbid disorders would also be desirable, in particular trials specifying
ADHD symptom measures as their primary endpoint, as would
more studies of atomoxetine in very young patients.
In conclusion, atomoxetine is an effective and generally well
tolerated option for the treatment of ADHD in children and
adolescents, and is not classified as a stimulant. Atomoxetine
showed efficacy in children and adolescents with ADHD in well
designed placebo-controlled trials, with mixed results seen in
active comparator trials; atomoxetine did not differ significantly
from or was noninferior to immediate-release methylphenidate
and was significantly less effective than osmotically released
methylphenidate or extended-release mixed amfetamine salts. It
can be administered either as a single daily dose or split into two
evenly divided doses, has a negligible risk of abuse or misuse, and
is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse or misuse, as
well as those who have co-morbid anxiety or tics, or who do not
wish to take a controlled substance. Thus, atomoxetine is a useful
option in the treatment of ADHD in children and adolescents.
Disclosure
The preparation of this review was not supported by any external
funding. During the peer review process, the manufacturer of the agent
under review was offered an opportunity to comment on this article.
224
Changes resulting from any comments received were made on the basis of
scientific and editorial merit.
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Correspondence: Karly P. Garnock-Jones, Wolters Kluwer Health | Adis,

41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754,
Auckland, New Zealand.
E-mail: demail@adis.co.nz

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Pediatr Drugs 2009; 11 (3): 203-226

ADIS DRUG EVALUATION

2009 Adis Data Information BV. All rights reserved.

Garnock-Jones & Keating

7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

2009 Adis Data Information BV. All rights reserved.

Pediatr Drugs 2009; 11 (3)

factors.[2,4,6] Dopamine and norepinephrine (noradrenaline)

Garnock-Jones & Keating

profile of oral atomoxetine in children and adolescents with

dopamine levels in the nucleus accumbens and striatum remained

2.2 Other Effects

Atomoxetine was associated with modest increases in heart

Garnock-Jones & Keating

aged 714 years with a DSM-IV diagnosis of ADHD who

Oral atomoxetine is rapidly absorbed; Cmax (144 ng/mL) was

2009 Adis Data Information BV. All rights reserved.

adolescents; however, atomoxetine may be administered with or

Atomoxetine undergoes extensive biotransformation.[10] In

Extensive metabolizers with moderate (Child-Pugh class B)

Pediatr Drugs 2009; 11 (3)

Extensive metabolizers with end-stage renal disease showed no

The efficacy of oral atomoxetine was compared with that of

duration investigated the efficacy of atomoxetine versus placebo

Patients in the short-term trials were randomized to receive

Garnock-Jones & Keating

ADHD-Rating Scale (ADHD-RS)

Child Health and Illness Profile-Child,

Childrens Health Questionnaire (CHQ)

50-item parent-rated quality-of-life rating scale, measuring 14 physical and

Clinical Global Impressions-Improvement

Clinical Global Impressions-ADHD-Severity

Clinical Global Impressions-Severity scale

Conners Parent/Teacher Rating Scale

Daily Parent Ratings of Evening and

13-item parent-completed questionnaire, examining behavior in the morning and

Daily Parent Ratings of Evening and

11-item parent-completed questionnaire, examining behavior in the morning (3 items)

Pediatric Quality of Life Inventory (PedsQL)

Swanson, Kotkin, Agler, M-Flynn, and

13-item rating scale representing classroom behavior (6 deportment items, 7 attention

Swanson, Nolan, and Pelham Rating

(7090%),[37-43] and 4861% had received previous stimulant

placebo than atomoxetine recipients; this was shown to have no

Age of pts Treatmenta

Mean ADHD- Mean change from baseline in

p < 0.05, ** p < 0.01, *** p 0.001 vs PL.

2009 Adis Data Information BV. All rights reserved.

Pediatr Drugs 2009; 11 (3)

Garnock-Jones & Keating

effect compared with placebo. One study[43] reported significant

4.1.2 Longer Term Treatment

A multicenter study has investigated longer term atomoxetine

Mean total ADHD scores increased to a significantly smaller

psychoactive medication;[59,60] a need for immediate pharmacotherapy;[59] and psychotherapy.[59,60]

Garnock-Jones & Keating

MPH 560 mg/day

ATO 0.81.8 mg/kg/day

OR MPH 1854 mg/day

ATO 0.51.8 mg/kg/day

ATO 0.81.8 mg/kg/day

MPH 0.20.6 mg/kg/day

ATO 0.51.4 mg/kg/day

MAS 1030 mg/day

p < 0.05, p < 0.01, * p 0.001 vs PL.